The Ebola virus causes a severe hemorrhagic fever with a 50-90% case fatality. No vaccines or treatments are available. Because of its extraordinary lethality and the danger of intentional misuse or accidental importation, the Ebola virus is a category A pathogen and a high priority of biodefense efforts. The Ebola virus can be classified by antibody reactivity into four subtypes, two of which (Zaire and Sudan) are the most pathogenic and most frequently linked to human outbreaks. The Sudan subtype has been linked to four outbreaks including the largest Ebola virus outbreak yet documented (Uganda, 2000-2001) and a recent outbreak in Sudan in 2004. Administration of well-characterized, neutralizing monoclonal antibodies can confer immediate protection in case of viral exposure. However, all monoclonal antibodies with efficacy against Ebola virus have been raised to the Zaire subtype and those specific for only one epitope are known to cross-react to the Sudan Boniface strain. None react to the contemporary Sudan Gulu strain. Here we propose to develop and characterize monoclonal antibodies against the Sudan subtype of the Ebola virus (strains Gulu and Boniface). Epitopes will be mapped by protein biochemistry and x-ray crystallography, and antibodies will be tested for efficacy in mouse and non-human primate models. Through an interactive, multidisciplinary effort, we will combine structural and functional studies in order to determine which structural features on GP can elicit potent, neutralizing antibodies and to provide the necessary, fully characterized candidate immunotherapeutics for biodefense. Our extensive preliminary data demonstrate the feasibility of these specific aims.